There is disclosed in WO 96/11911 a class of novel compounds active as inhibitors of the activity of the 5-lipoxygenase enzyme, characterized by the following structural Formula (1.1.0): 
wherein:
-Ar1 is a heterocyclic moiety selected from the group consisting of imidazolyl; pyrrolyl; pyrazolyl; 1,2,3-triazotyl; 1,2,4-triazolyl; indolyl; indazolyl; and benzimidazolyl; bonded to X1 through a ring nitrogen atom; and substituted with 0-2 substituents selected from the group consisting of halo; hydroxy; cyano; amino; (C1-C4) alkyl; (C1-C4) alkoxy; (C1-C4) alkylthio; (C1-C4) halo-substituted alkyl; (C1-C4) halo-substituted alkoxy; (C1-C4) alkylamino; and di(C1-C4) alkylamino;
-X1 is a direct bond or (C1-C4) alkylene;
-Ar2 is phenylene substituted with 0-2 substituents selected from the group consisting of halo; hydroxy; cyano; amino; (C1-C4) alkyl; (C1-C4) alkoxy; (C1-C4) alkylthio; (C1-C4) halo-substituted alkyl; and (C1-C4) halo-substituted alkoxy;
-X2 is -A-X- or -X-A wherein A is a direct bond or (C1-C4) alkylene and X is oxy; thio; sulfinyl; or sulfonyl;
-Ar3 is a member selected from the group consisting of phenylene; pyridylene; thienylene; furylene; oxazolylene; and thiazolylene; substituted with 0-2 substituents selected from halo; hydroxy; cyano; amino; (C1-C4) alkyl; (C1-C4) alkoxy; (C1-C4) alkylthio; (C1-C4) halo-substituted alkyl; (C1-C4) halo-substituted alkoxy; (C1-C4) alkylamino; and di(C1-C4) alkylamino;
-R1 and R2 are each (C1-C4) alkyl; or together they form a group of formula: -D1-Z-D2- which together with the carbon atom to which it is attached defines a ring having 3 to 8 atoms, wherein D1 and D2 are (C1-C4) alkylene and Z is a direct bond or oxy; thio; sulfinyl; sulfonyl; or vinylene; and D1 and D2 may be substituted by (C1-C3) alkyl; and
-Y is CONR3R4; CN; C(R3)xe2x95x90Nxe2x80x94OR4; COOR3; COR3; or CSNR3R4; wherein
xe2x80x94R3 and R4 are each H or (C1-C4) alkyl.
With respect to the above-rected compounds, the preferred meaning for (C1-C4) halo-substituted alkyl is trifluoromethyl; and the preferred meaning for (C1-C4) halo-substituted alkoxy is trifluoromethoxy. A preferred group of the above-recited compounds consists of those wherein Ar2 is 1,4-phenylene and Ar3 is 1,3-phenylene or 5-fluoro-1,3-phenylene. Within said preferred group, more preferred compounds are those in which Ar1 is 2-alkylimidazolyl; X1 is a direct bond; and Y is CONH2; and those in which Ar1 is pyrroyl; X1 is CH2; and Y is CONH2.
A particularly preferred embodiment of the above-described class of inhibitory compounds is the following compound of Formula (1.0.0): 
Compounds which inhibit the action of lipoxygenase enzyme are useful in the treatment or alleviation of inflammatory diseases, allergy and cardiovascular diseases in mammals including humans. Lipoxygenase enzyme activity occurs as part of the arachidonic acid cascade. Arachidonic acid is the biological precursor of several groups of biologically active endogenous metabolites. Arachidonic acid is first released from membrane phospholipids via the action of phospholipase A2. Arachidonic acid is then metabolized (i) by cyclooxygenase to in give prostaglandins including prostacyclin, and thromboxanes; or (ii) by lipoxygenase to give hydroperoxy fatty acids, which may be further converted to leukotrienes.
Leukotrienes, in turn, are extremely potent and elicit a wide variety of biological effects, e.g., peptidoleukotrienes, LTC4, LTD4, and LTE4, are important bronchoconstrictors and vaso-constrictors, and cause plasma extravasation by increasing capillary permeability. LTB4 is a potent chemotacbic agent which intensifies leukocyte infiltration and degranulation at a site of inflammation. Leukotrienes have been implicated in a number of human disease states including asthma, chronic obstructive pulmonary disease, allergic rhinitis, rheumatoid arthritis, gout, psoriasis, atopic dermatitis, adult respiratory distress syndrome (ARDS), and inflammatory bowel diseases including. Crohn""s disease. An agent which actively inhibits lipoxygenases, and as a consequence the production of leukotrienes, will be of significant therapeutic value in treating acute and chronic inflammatory conditions. See Masamune and Melvin, Annual Repoits in Medicinal Chemistry 24, 71-80 (1989). Particular lipoxygenase inhibitors have been disclosed in EP 0 462 830; EP 0 505 122; and EP 0 540 165.
Several preparation processes for the lipoxygenase inhibitors described in above-mentioned published application WO 96/39408 are set forth therein. An example of such a preparation process is the coupling of a compound of Formula (1.2.0) and a compound of Formula (1.2.1), which may be represented by the reaction scheme set out below: 
where X1 is thio, and Q is a displaceable group in the presence of thiourea and a suitable catalyst, e.g., tetrakis(triphenylphosphine)-palladium. Reference is made to Chem. Lett., 1379-1380 (1986). Suitable displaceable groups Q are said to include a halo or sulfonyloxy group.
The present invention is in the field of methods used for synthetic preparation of compounds of the type of Formula (1.0.0), some of which are known compounds, some of which are novel compounds, and some of which are not in the public domain because they cannot be obtained using methods of preparation heretofore known in the art. All of the compounds, however, possess biological activity as inhibitors of 5-lipoxygenase.
As already noted above, it is known in the art that compounds of the type in Formula (1.0.0) may be prepared by a process which initially uses a palladium catalyzed nucleophilic substitution of aryl halides by thiolate anions or thiols themselves. As in the Williamson reaction, which is the best general method for preparing unsymmetrical as well as symmetrical ethers, yields are improved by phase transfer catalysis. For a detailed treatment of the use of phase transfer catalysis in the preparation of sulfur-containing compounds, see, e.g., Weber; Gokel Phase Transfer Catalysis in Organic Synthesis, Springer; New York, 221-233 (1977). Further details concerning the initial stage of the process of the present invention may be found in Migita et al., Bull. Chem. Soc. Japan 53, 1385-1389 (1980). Said initial stage may be represented by the following reaction scheme: 
where X is I or Br; and R is phenyl or (C1-C4) alkyl.
The technical literature contains a number of disclosures relating to palladium-catalyzed synthesis. See, e.g., Brocato et al., Tetrahedron Lett. 33, 7433 (1992), which describes ring formation based on the palladium-, especially Pd(PPh3)4,-catalyzed reaction of bifunctional aromatic compounds with terminal alkynes and carbon monoxide, requiring both palladium(0) and palladium(II) catalysts.
Arcadi et al., Tetrahedron Lett. 34, 2813 (1993) discloses synthesis of 2,3,5-trisubstituted furans from aryl halides and 2-propargyl-1,3-dicarbonyl compounds in the presence of tetrakis(triphenylphosphine)palladium(0) and K2CO3. The authors observe that the nature of the base strongly affects the reaction course.
McClure and Danishefsky, J. Am. Chem. Soc. 115, 6094-6100 (1993) discloses synthesis of 1,5-epoxybenzazocine congeners in 90% yield using catalytic tetrakis(triphenylphosphine)-palladium(0) in acetonitrile containing triethylamine.
Nuss et al, J. Am. Chem. Soc. 115, 6991-6992 (1993) discloses synthesis of neocarzinostatin chromophore analogs using catalytic tetrakis(triphenylphosphine)-palladium(0) in THF and alkynyl stannane reactants.
Paquette and Astles, J. Org. Chem. 58, 165-169 (1993) discloses synthesis of furanocembranolides with side chain extension mediated by palladium(0) catalyzed coupling to vinylstannane performed in refluxing benzene or dimethoxyethane. The authors note that the reaction is solvent-dependent, with a change to chloroform being particularly beneficial.
The technical literature also contains a number of disclosures relating to the use of other transition metals in addition to palladium to catalyze reactions. See, e.g., Takagi, Chemistry Letters, 2221-2224 (1987), which discloses the use of nickel(0) and palladium(0) complexes as catalysts in the synthesis of diaryl sulfides from aryl halides and aromatic thiols.
None of the above-described references, however, discloses or suggests the particular processes of preparation of the present invention, which are both facile and efficient, while at the same time affording acceptable yields not achievable heretofore.
The present invention is concerned with processes of preparation where a number of the ultimate products of said processes are known compounds of demonstrated utility as 5-lipoxygenase inhibitors. The present invention additionally concerns a number of other ultimate final products of said processes which have not been known heretofore because they were synthetically inaccessible prior to the availability of said processes of the present invention. These novel final products are also useful as 5-lipoxygenase inhibitors, as described in detail further herein. All of said processes of preparation of the present invention are recited in summary in the paragraphs immediately below.
A key intermediate used in the processes of preparation of the present invention is tetrahydro-4-[3-(4-fluorophenyl)-thio]phenyl-2H-pyran-4-carboxamide of Formula (2.0.0): 
The present invention is thus also concerned with a process for preparing a compound of Formula (2.0.0), which may be illustrated by the following Synthesis Scheme (10.0.0) 
comprising:
(a) establishing a reaction mixture consisting of
(1) tetrahydro-4-(3-bromo or iodo-phenyly)-2H-pyran-4-nitrile of Formula (3.0.0): 
where X is bromo or iodo;
and
(2) 4-fluorothiophenol of Formula (4.0.0): 
(3) in a solvent consisting of a straight or branched chain aliphatic alcohol having a total of from 2 to 7 carbon atoms, optionally as an aqueous mixture thereof; and more preferably where said alcohol is a secondary alcohol selected from the group consisting of isopropyl alcohol, sec-butyl alcohol, iso-pentyl alcohol, and 2-heptanol, optionally as an aqueous mixture of said secondary alcohol;
(4) in the presence of strong base of Formula (5.0.0):
Mxe2x80x94Oxe2x80x94R5xe2x80x83xe2x80x83(5.0.0)
where
M is an alkali metal, Group 1/la element, selected from the group consisting of lithium, Li; sodium,Na; potassium, K; rubidium, Rb; and cesium, Cs; and
R5 is hydrogen, H; or straight or branched chain (C1-C4) alkyl; preferably a member selected from the group consisting of lithium hydroxide, LiOH; sodium hydroxide, NaOH; potassium hydroxide, KOH; rubidium hydroxide, RbOH; cesium hydroxide, CsOH; lithium methoxide, LiOCH3; sodium methoxide, NaOCH3; potassium methoxide, KOCH3; rubidium methoxide, RbOCH3; cesium methoxide, CsOCH3; lithium ethoxide, LiOCH2CH3; sodium ethoxide, NaOCH2CH3; potassium ethoxide, KOCH2CH3; rubidium ethoxide, RbOCH2CH3; cesium ethoxide, CsOCH2CH3; lithium teit-butoxide, LiOC(CH3)3; sodium teit-butoxide, NaOC(CH3)3; potassium tert-butoxide, KOC(CH3)3; rubidium tert-butoxide, RbOC(CH3)3, and cesium tert-butoxide, CsOC(CH3)3; including mixtures of the above;
and further
(5) in the presence of a transition metal catalyst comprising a palladium metal complex which preferably is a member selected from the group consisting of
tetrakis(triphenylphosphine)palladium(0), [(C6H5)3P]4Pd(0);
tetrakis(methyidiphenylphosphine)palladium(0), [(C6H5)2PCH3]4Pd(0);
trans-dichlorobis(methyldiphenylphosphine)palladium(II), [(C6H5)2PCH3]2PdCl2;
dichlorobis[methylenebis(diphenylphosphine)]dipaadium-dichlorome thane adduct;
dichlorobis(triphenylphosphine)palladium(II), [(C6H5)3P]2PdCl2;
tris(dibenzylideneacetone)dipalladium(0)-chloroform adduct, (C6H5CHxe2x95x90CHCOCHxe2x95x90CHC6H5)3Pd2.CHCl3;
bis(dibenzylideneacetone)palladium(0), (C6H5CH=CHCOCH=CHC6H5)2Pd;
[1,1xe2x80x2-bis(diphenylphosphino)ferrocene]dichloropalladium(II), complex with dichloromethane
bis[1,2-bis(diphenylphosphino)ethane]palladium(0); and
(xcfx80-allyl)palladium(II) chloride dimer;
followed by
(b) healing said reaction mixture, preferably at reflux, preferably for a period of from 12 to 36 hours, more preferably from 18 to 24 hours; whereby there is produced said compound of Formula (2.0.0) which is optionally isolated using conventional separation techniques.
The above-described process of preparation in which the 4-carboxamide portion of the pyran moiety is formed during the thio-addition step is a preferred manner of carrying out this portion of the process of the present invention. A useful alternative embodiment comprises formation of the 4-carboxamide portion of the pyran moiety before the step of thio-addition is carried out. Said alternative embodiment of this portion of the process of the present invention involves a process for preparing a compound of Formula (2.0.0) which may be illustrated by the following Synthesis Scheme (10.1.0): 
comprising:
(a) establishing a reaction mixture consisting of
(1) tetrahydro-4-(3-bromo or iodophenyl)-2H-pyran-4-nitrile of Formula (3.0.0): 
where X is bromo or iodo;
(2) in a solvent consisting of an alcohol as defined above, optionally as an aqueous mixture thereof, preferably a secondary alcohol as defined above; more preferably isopropyl alcohol; optionally as an aqueous mixture of said secondary alcohol;
(3) in the presence of strong base of Formula (5.0.0):
Mxe2x80x94Oxe2x80x94R5xe2x80x83xe2x80x83(5.0.0)
where M and R5 are as defined above; preferably wherein said strong base is sodium hydroxide, NaOH; potassium hydroxide, KOH; sodium ethoxide, NaOCH2CH3; or potassium tert-butoxide, KOC(CH3)3;
followed by
(b) heating said reaction mixture, preferably at reflux, preferably for a period of from 3 to 8 hours, more preferably from 5 to 6 hours; whereby there is produced a compound of Formula (3.1.0): 
where X is bromo or iodo;
followed by
(c) forming a reaction mixture consisting of said compound of Formula (3.1.0) and 4-fluorothiophenol of Formula (4.0.0): 
(1) in a solvent consisting of an alcohol as defined above, optionally as an aqueous mixture thereof; preferably a secondary alcohol as defined above; more preferably iso-propyl alcohol;
optionally as an aqueous mixture of said secondary alcohol;
(2) in the presence of a strong base of Formula (5.0.0):
xe2x80x83Mxe2x80x94Oxe2x80x94R5xe2x80x83xe2x80x83(5.0.0)
where M and R5 are as defined above; preferably wherein said strong base is sodium hydroxide, NaOH; potassium hydroxide, KOH; sodium ethoxide, NaOCH2CH3; or potassium tert-butoxide, KOC(CH3)3;
and further
(3) in the presence of a transition metal catalyst comprising a palladium metal complex, which is preferably a member selected from the group consisting of
tetrakis(triphenylphosphine)palladium(0), [(C6H5)3P]4Pd(0);
tetrakis(methyldiphenylphosphine)palladium(0), [(C6H5)2PCH3]4Pd(0);
transdichlorobis(methyldiphenylphosphine)palladium(II), [C6H5)2PCH3]2PdCl2;
dichlorobis[methylenebis(diphenylphosphine)]dipalladium-dichioromethane adduct;
dichlorobis(triphenylphosphine)palladium(II), [(C6H5)3P]2PdCl2;
tris(dibenzylideneacetone)dipalladium(0)-chloroform adduct, (C6H5CHxe2x95x90CHCOCHxe2x95x90CHC6H5)3Pd2.CHCl3;
bis(dibenzylideneacetone)palladium(0), (C6H5CHxe2x95x90CHCOCHxe2x95x90CHC6H5)2Pd;
[1,1xe2x80x2-bis(diphenylphosphino)ferrocene]dichloropalladium(II), complex with dichloromethane
bis[1,2-bis(diphenylphosphino)ethane]palladium(0); and
(xcfx80-allyl)palladium(II) chloride dimers
followed by
(d) heating said reaction mixture, preferably at reflux, preferably for a period of from 5 to 15 hours, more preferably from 8 to 10 hours; whereby there is produced said compound of Formula (2.0.0)
The present invention is still further concerned with a process for preparing a compound of Formula (1.3.0): 
which may be illustrated by the following Synthesis Scheme (10.2.0): 
where
the moiety of following Formula (1.3.1): 
is an electron deficient monocydic or benzo-fused bicyclic N-heterocyclic group containing two nitrogen atoms, of Formula (1.3.2) (1.3.3), (1.3.4) or (1.3.5): 
where
xe2x80x9c*xe2x80x9d is a symbol which represents the point of attachment of the moiety of Formula (1.3.2) (1.3.3, (1.3.4) or (1.3.5);
R7 and R8 are independently selected from the group consisting of H; straight or branched chain (C1-C4) alkyl; and (C6-C10) aryl; wherein said alkyl and aryl groups are substituted by 0 to 2 substituents selected from the group consisting of halo; hydroxy; cyano; amino; (C1-C4) alkyl; (C1-C4) alkoxy; (C1-C4) alkylthio; (C1-C4) halo-substituted alkyl; (C1-C4) halo-substituted alkoxy; (C1-C4) alkylamino; and di(C1-C4) alkylamino;
comprising:
(a) establishing a reaction mixture consisting of
(1) tetrahydro-4-[3-(4-fluorophenyl)-thio]phenyl-2H-pyran-4-carboxamide of Formula (2.0.0): 
and
(2) an electron deficient monocyclic or benzo-fused bicyclic N-heterocycle containing two nitrogen atoms, of Formula (1.3.6) (1.3.7), (1.3.8) or (1.3.9): 
where R7 and R8 have the same meaning as set out above;
(3) in an aprotic solvent, preferably dimethylsulfoxide (DMSO);
(4) in the presence of a strong base in solid form selected from the group consisting of sodium hydroxide, NaOH; and potassium hydroxide, KOH;
and optionally
(5) in the presence of a catalytic amount of cesium carbonate, Cs2CO3, or of a phase transfer catalyst, preferably a member selected from the group consisting of cetyltrimethylammonium bromide (CTMAB); dibenzo-18-crown-6 (DB-18-c-6); dicyclohexano-18-crown-6 (DC-18-c-6); 18-crown-6 (18-c-6); (xe2x88x92)-N-dodecyl-N-methylpyridinium bromide (DMCOH); hexamethyl phosphoric triamide (HlM PT); cetylpyridinium bromide (NCPB); N-benzyiquininium chloride (QUIBEC); tetra-n-butylammonium bromide (TBAB); tetra-n-butylammonium chloride (TBAC); tetra-n-butylammonium hydroxide (TBAH); tetra-n-butylammonium hydrogen sulfate (TBAHS); tetra-n-butylammonium iodide (TBAI); tetra-ethylammonium chloride hydrate (TEAC); tri-n-butylamine (TBA); benzyltributylammonium bromide (TBBAB); hexadecyltributylphosphonium bromide (TBHDPB); benzyltriethylammonium bromide (TEBAB); benzyltriethylammonium chloride (TEBA); hexadecyltriethylammonium chloride (TEHDAC); tetramethylammonium chloride (TMAC); hexadecyltrimethylammonium chloride (TMHDAC); and octyltrimethylammonium chloride (TMOAC); and more preferably a quatemary ammonium salt or a phosphonium salt comprising a member of the aboverecited group;
followed by
(b) heating said reaction mixture, preferably at reflux, under a nitrogen atmosphere; whereby there is produced a compound of Formula (1.3.0).
The present invention is further concerned with the above-recited method of preparing a compound of Formula (1.3.0), wherein said compound of Formula (1.3.0) is a member selected from the group consisting of:
Tetrahydro-4-{3-[4-(2-methyl-1H-imidazol-1-yl)phenyl]thio}phenyl-2H-pyran-4-carboxamide;
Tetrahydro-4-{3-[4-(1H-imidazol-1-yl)phenyl]thio}phenyl-2H-pyran-4-carboxamide;
Tetrahydro-4-{3-[4-(1H-benzoimidazol-1-yl)phenyl]thio}phenyl-2H-pyran-4-carboxamide
Tetrahydro-4-{3-[4-(1H-pyrazol-1-yl)phenyl]thio}phenyl-2H-pyran-4-carboxamide; and
Tetrahydro-4-{3-[4-(4-methyl-1H-pyrazol-1-yl)pheny]thio}phenyl-2H-pyran-4-carboxamide
The above-mentioned final products have not been known heretofore because they have been synthetically inaccessible prior to the availability of the processes of the present invention. These novel final products are also useful as 5-lipoxygenase inhibitors, and consist of a member selected from the group consisting of:
Tetrahydro-4-{3-[4-(1H-imidazol-1-yl)pheny]thio}phenyl-2H-pyran-4-carboxamide;
Tetrahydro-4-{3-[4-(1H-benzoimidazol-1-yl)phenyl]thio}phenyl-2H-pyran-4-carboxamide
Tetrahydro-4-{3-[4-(1H-pyrazol-1-yl)pheny]thio}phenyl-2H-pyran-4-carboxamide; and
Tetrahydro-4-{3-[4-(4-methyl-1H-pyrazol-1-yl)phenyl]thio}phenyl-2H-pyran-4-carboxamide.
The present invention is still further concerned with a process for preparing a compound of Formula (1.0.0): 
comprising:
(a) establishing a reaction mixture consisting of
(1) tetrahydro-4-[3-(4-fluorophenyl)-thio]phenyl-2H-pyran-4-carboxamide of Formula (2.0.0) 
(2) 2-methylimidazole;
(3) in an aprotic solvent, preferably dimethylsulfoxide (DMSO);
(4) in the presence of a strong base in solid form selected from the group consisting of sodium hydroxide, NaOH; and potassium hydroxide, KOH;
and optionally
(5) in the presence of a catalytic amount of cesium carbonate, Cs2CO3, or of a phase transfer catalyst, preferably a member selected from the group consisting of cetyltrimethylammonium bromide (CTMAB); dibenzo-18-crown-6 (DB-18-c-6); dicyclohexano-18-crown-6 (DC-18-c-6); 18-crown-6 (18-c-6); (xe2x88x92)-N-dodecyl-N-methylpyridinium bromide (DMCOH); hexamethyl phosphoric triamide (HMPT); cetylpyridinium bromide (NCPB); N-benzylquininium chloride (QUIBEC); tetra-n-butylammonium bromide (TBAB); tetra-n-butylammonium chloride (TBAC); tetra-n-butylammonium hydroxide (TBAH); tetra-n-butylammonium hydrogen sulfate (TBAHS); tetra-n-butylammonium iodide (TBAI); tetra-ethylammonium chloride hydrate (TEAC); tri-n-butylamine (TBA); benzyltributylammonium bromide (TBBAB); hexadecyltributylphosphonium bromide (TBHDPB); benzyltriethylammonium bromide (TEBAB); benzyltriethylammonium chloride (TEBA); hexadecyltriethylammonium chloride (TEHDAC); tetramethylammonium chloride (TMAC); hexadecyltrimethylammonium chloride (TMHDAC); and octyltrimethylammonium chloride (TMOAC); and more preferably a quaternary ammonium salt or a phosphonium salt comprising a member of the above-recited group;
followed by
(b) heating said reaction mixture, preferably at reflux, preferably from 115xc2x0 to 145xc2x0 C., more preferably from 125xc2x0 to 130xc2x0 C., under a nitrogen atmosphere, preferably for from 12 to 30 hours, more preferably for from 17 to 24 hours; whereby there is produced said compound of Formula (1.3.0).
The present invention is still further concerned with a process for preparing a substantially pure mesylate salt of Formula (1.0.1): 
which may be illustrated by the following Synthesis Scheme (10.3.0): 
comprising:
(a) preparing a compound of Formula (2.0.0): 
comprising:
(1) establishing a reaction mixture consisting of
(i) tetrahydro-4-(3-bromophenyl)2H-pyran-4-nitrile of Formula (3.2.0): 
and
(ii) 4-fluorothiophenol of Formula (4.0.0): 
(iii) in a solvent selected from the group consisting of iso-propyl alcohol, sec-butyl alcohol, iso-pentyl alcohol, and 2-heptanol, preferably isopropyl alcohol, optionally as an aqueous mixture thereof;
(iv) in the presence of a strong base selected from the group consisting of sodium hydroxide, NaOH; and potassium hydroxide, KOH;
and further
(v) in the presence of a transition metal catalyst comprising a member independently selected from the group consisting of palladium metal complexes; preferably wherein said palladium metal complex is a member selected from the group consisting of
tetrakis(triphenylphosphine)palladium(0), [(C6H5)3P]4Pd(0);
tetrakis(methyidiphenylphosphine)palladium(0), [(C6H5)2PCH3]4Pd(0);
trans-dichlorobis(methyldiphenylphosphine)palladium(Ii), [(C6H5)2PCH3]2PdCl2;
dichlorobis[methylenebis(diphenylphosphine)]dipalladium-dichloromethane adduct;
dichlorobis(triphenylphosphine)palladium(II), [(C6H5)3P]2PdCl2;
tris(dibenzylideneacetone)dipalladium(0)-chloroform adduct, (C6H5CHxe2x95x90CHCOCHxe2x95x90CHC6H5)3Pd2.CHCl3;
bis(dibenzylideneacetone)palladium(0), (C6H5CHxe2x95x90CHCOCHxe2x95x90CHC6H5)2Pd;
[1,1xe2x80x2-bis(diphenylphosphino)ferrocene]dichloropalladium(II), complex with dichioromethane
bis[1,2-bis(diphenylphosphino)ethane]palladium(II); and
(xcfx80-allyl)palladium(II) chloride dimer;
followed by
(2) heating said reaction mixture at reflux of from 80xc2x0 to 84xc2x0 C. for a period of from 18 to 30 hours, preferably 24 hours; whereby there is produced said compound of Formula (2.0.0);
(b) establishing a reaction mixture consisting of said compound of Formula (2.0.0) and a compound of Formula (1.3.10): 
(1) in an aprobe solvent which is preferably dimethylsulfoxide (DMSO);
(2) in the presence of a strong base in solid form selected from the group consisting of sodium hydroxide, NaOH; and potassium hydroxide, KOH;
and optionally
(3) in the presence of a catalytic amount of cesium carbonate, Cs2CO3, or of a phase transfer catalyst, preferably a member selected from the group consisting of cetyltrimethylammonium bromide (CTMAB); dibenzo-18-crown-6 (DB-18-c-6); dicyclohexano-18-crown-6 (DC-18-c-6); 18-crown-6 (18-c-6); (xe2x88x92)N-dodecyl-N-methylpyridinium bromide (DMCOH); hexamethyl phosphoric triamide (HMPT); cetylpyridinium bromide (NCPB); N-benzylquininium chloride (QUIBEC); tetra-n-butylammonium bromide (TBAB); tetra-n-butylammonium chloride (TBAC); tetra-n-butylammonium hydroxide (TBAH); tetra-n-butylammonium hydrogen sulfate (TBAHS); tetra-n-butylammonium iodide (TBAI); tetra-ethylammonium chloride hydrate (TEAC); tri-n-butylamine (TBA); benzyltributylammonium bromide (TBBAB); hexadecyltributylphosphonium bromide (TBHDPB); benzyltriethylammonium bromide (TEBA8); benzyltriethylammonium chloride (TEBA); hexadecyltriethylammonium chloride (TEHDAC); tetramethylammonium chloride (TMAC); hexadecyltrimethylammonium chloride (TMHDAC); and octyltrimethylammonium chloride (TMOAC); and more preferably a quaternary ammonium salt or a phosphonium salt comprising a member of the above-recited group;
followed by
(c) heating said reaction mixture at reflux, under a nitrogen atmosphere; whereby there is produced a compound of Formula (1.0.0): 
followed by
(d) forming a concentrated methanol solution of said compound of Formula (1.0.0) which is then filtered, preferably through activated carbon, after which there is then added to the filtrate methanesulfonic acid, MeSO3H; followed by further concentration and the addition of ethyl acetate ad senatim until a crystalline product is isolated comprising substantially pure mesylate salt of Formula (1.0.1) 
or, alternatively, followed by
(e) forming a concentrated methanol solution of said compound of Formula (1.0.0) to which there is then added methanesulfonic acid, MeSO3H; followed by filtering of the mixture, preferably through activated carbon, after which there follows further concentration and the addition of ethyl acetate ad seiatim until a crystalline product is isolated comprising substantially pure mesylate salt of Formula (1.0.1) 
The present invention involves an improved process for preparing known compounds of demonstrated utility as a 5-lipoxygenase inhibitors, and in particular the compound of Formula (1.0.0): 
Further, the present invention involves preparation of a number of other compounds which have not been known heretofore because they were synthetically inaccessible prior to the availability of the improved process of the present invention. These novel compounds are also useful as 5-lipoxygenase inhibitors, and include, among others, the following compounds of Formulas (1.1.1); (1.1.2); (1.1.3); and (1.1.4):
Tetrahydro-4-{3-[4-(1H-imidazol-1-yl)phenyl]thio}phenyl-2H-pyran-4-carboxamide: 
Tetrahydro-4-{3-[4-(1H-benzoimidazol-1-yl)phenyl]thio}phenyl-2H-pyran-4-carboxamide: 
Tetrahydro-4-{3-[4-(1H-pyrazol-1-yl)pheny]thio}phenyl-2H-pyran-4-carboxamide: 
and
Tetrahydro-4-{3-[4-(4-methyl-1H-pyrazol-1-yl)phenyl]thio}phenyl-2H-pyran-4-carboxamide. 
In order to prepare the above-mentioned compounds of Formulas (1.1.1)-(1.1.4) and similar compounds of this type, it is advantageous to use the following process of the present invention for preparing a compound of Formula (1.3.0): 
where
the moiety of Formula (1.3.1): 
is an electron deficient monocyclic or benzo-fused bicyclic N-heterocyclic group containing two nitrogen atoms, of Formula (1.3.2) (1.3.3), (1.3.4) or (1.3.5): 
where
xe2x80x9c*xe2x80x9d is a symbol which represents the point of attachment of the moiety of Formula (1.3.2) (1.3.3, (1.3.4) or (1.3.5);
R7 and R8 are independently selected from the group consisting of H; straight or branched chain (C1-C4) alkyl; and (C6-C10) aryl; wherein said alkyl and aryl groups are substituted by 0 to 2 substituents selected from the group consisting of halo; hydroxy; cyano; amino; (C1-C4) alkyl; (C1-C4) alkoxy; (C1-C4) alkylthio; (C1-C4) halo-substituted alkyl; (C1-C4) halo-substituted alkoxy; (C1-C4) alkylamino; and di(C1-C4) alkylamino.
The above-mentioned embodiment of the preparation process of the present invention may be illustrated by following Synthesis Scheme (10.2.0): 
is an electron deficient monocyclic or benzo-fused bicyclic N-heterocycle containing two nitrogen atoms, of Formula (1.3.6) (1.3.7), (1.3.8) or (1.3.9), as defined further above.
Accordingly, the above-mentioned process of the present invention illustrated in Synthesis Scheme (10.2.0) may be carried out by:
(a) establishing a reaction mixture consisting of
(1) tetrahydro-4-[3-(4-fluorophenyl)-thio]phenyl-2H-pyran-4-carboxamide of Formula (2.0.0): 
and
(2) an electron deficient monocyclic or benzo-fused bicyclic N-heterocycle containing two nitrogen atoms, of Formula (1.3.6) (1.3.7), (1.3.8) or (1.3.9): 
where R7 and R8 have the same meaning as set out above;
(3) in an aprotic solvent, preferably a member selected from the group consisting essentially of hexane; 1,4-dioxane; carbon tetrachioride; benzene; toluene; xylenes; diethyl ether; chloroform; ethyl acetate; tetrahydrofuran (THF); methylene chloride; hexamethylphosphoric triamide (HMPT); nitrornethane; N,N-dimethylformamide (DMF); acetonitrile; sulfolane; and dimethylsulfoxide (DMSO); more preferably dimethylsulfoxide (DMSO);
(4) in the presence of a strong base in solid form selected from the group consisting of sodium hydroxide, NaOH; and potassium hydroxide, KOH;
and optionally
(5) in the presence of a catalytic amount of cesium carbonate, Cs2CO3, or of a phase transfer catalyst, preferably a member selected from the group consisting of cetyltrimethylammonium bromide (CTMAB); dibenzo-18-crown-6 (DB-18-c-6); dicyclohexano-18-crown-6 (DC-18-c-6); 18-crown-6 (18-c-6); (xe2x88x92)-N-dodecyl-N-methylpyridinium bromide (DMCOH); hexamethyl phosphoric triamide (HMPT); cetylpyridinium bromide (NCPB); N-benzylquininium chloride (QUIBEC); tetra-n-butylammonium bromide (TBAB); tetra-n-butylammonium chloride (TBAC); tetra-n-butylammonium hydroxide (TBAH); tetra-n-butylammonium hydrogen sulfate (TBAHS); tetra-n-butylammonium iodide (TBAI); tetra-ethylammonium chloride hydrate (TEAC); tri-n-butylamine (TBA); benzyltributylammonium bromide (TBBAB); hexadecyltributylphosphonium bromide (TBHDPB); benzyltriethylammonium bromide (TEBAB); benzyltriethylammonium chloride (TEBA); hexadecyltriethylammonium chloride (TEHDAC); tetramethylammonium chloride (TMAC); hexadecyltrimethylammonium chloride (TMHDAC); and octyltrimethylammonium chloride (TMOAC); and more preferably a quaternary ammonium salt or a phosphonium salt comprising a member of the above-recited group;
followed by
(b) heating said reaction mixture, preferably at reflux, under a nitrogen atmosphere; whereby there is produced said compound of Formula (1.3.0).
As the person of ordinary skill in the art of preparing organic compounds of the type with which the present invention is concerned will recognize, displacement of aryl fluoride in the presence of base by an electron deficient nitrogen heterocycle is a relatively unknown method of forming carbon-nitrogen bonds, and is clearly one which has not been suggested heretofore as useful in preparing the types of compounds in question. Normally a strong electron withdrawing group, e.g., nitro, positioned para or otho with respect to the fluorine atom, is required in order to achieve an acceptable level of displacement with a nitrogen nucleophile in the presence of base. Such displacement reactions typically afford only low yields, often require elevated temperatures and extended reaction times, and result in products requiring further purification. See, e.g., Morgan et al, J. Med. Chem., 33, 1091-1097 (1990), which discloses a preparation method in which the methyl or ethyl ester of 4-fluoro-benzoic acid is reacted with the appropriate imidazole in DMSO using a base such as K2CO3, NaOH, or NaH. The 4-(2-methyl-1H-imidazol-1-yl)-benzoic acid ethyl ester compound was obtained in only 33% yield of unrecrystallized product. By contrast, the processes of preparation of the present invention give high yields, a result which is a wholly unexpected one because the aryl fluoride reactant in the processes of the present invention has no electron withdrawing substituents attached to the aryl ring.
The most preferred solvent for use in the above-described process of the present invention is dimethylsulfoxide (DMSO), although any aprotic solvent is suitable, and those recited above are preferred. In another preferred embodiment of the process, solid sodium hydroxide, NaOH, is used in the reaction mixture for which DMSO is the solvent. The strong base in solid form which is employed in this step of the preparation process of the present invention, is selected from sodium hydroxide, NaOH and potassium hydroxide, KOH. The term xe2x80x9csolidxe2x80x9d used in this connection is intended to refer to the phase in which the strong base which is present is to be found in the reaction mixture. Preferably, said solid is used in a sub-divided as opposed to unitary form, thereby providing a more extensive surface area upon which the other reactants are able to contact the strong base during the process step involved. Thus, the strong base in solid form may be used as a powder or as pellets. It is not necessary, on the other hand, that the solid form of the strong base be finely sub-divided. The solid forms of the strong base preferably used in the processes of the present invention are readily commercially available.
It is optional, but preferred, in this aryl fluoride displacement step of the processes of the present invention that a catalytic amount of cesium carbonate, Cs2CO3, or of a phase transfer catalyst (xe2x80x9cPTCxe2x80x9d) also be employed. The amount used can vary between 0.5% and 10% mole, i.e., mole percent, but preferably will be between 1% and 5% mole. The amounts of catalyst which are suitable for use in the processes of the present invention can also be expressed as being in the range of from 0.005 to 0.5 equivalents, preferably from 0.01 to 0.1 equivalents, and more preferably about 0.05 equivalents, with reference to the other participants in the reaction.
Cesium carbonate, Cs2CO3, a material which is used as a catalyst in ethylene oxide polymerization and other catalyst assisted reactions, has been found to be a useful catalytic alternative to a phase transfer catalyst, as described herein.
The concentrations of the reactants in the same phase during this step can be less than optimal for convenient reaction rates to be achieved, and thus the use of a phase transfer catalyst can frequently be of benefit in reducing reaction temperatures and times. For example, when a phase transfer catalyst is used, the reaction may be carried out at 100xc2x0 C. with a reaction time of 28 hours. Correspondingly, when the reaction temperature is 130xc2x0 C. and a phase transfer catalyst is used, the reaction time is reduced to from 2 to 4 hours, with from 3 to 4 hours being required when a phase transfer catalyst is absent. It will be understood, nevertheless, that the present invention contemplates that solid NaOH or KOH may be used alone, ie., without the use of a phase transfer catalyst.
There are two principal types of phase transfer catalyst based on their mode of action. The first type comprises quatemary ammonium salts or phosphonium salts, while the second type comprises crown ethers and other cryptands. Quaternary ammonium salts may comprise, in addition to the more typical aliphatic configurations, compounds in which the quaternized nitrogen atom is part of a heterocyclic ring system, e.g., a pyridinium or quininium salts. The first type of phase transfer catalyst, i.e., quaternary ammonium salts or phosphonium salts, are preferred for use as the phase transfer catalyst in the preparation processes of the present invention. Of this type, the quatemary ammonium salts are more preferred, and among these the most preferred phase transfer catalysts comprise a member selected from the group consisting of tetra-n-butylammonium bromide (TBAB); tetra-n-butylammonium chloride (TBAC); tetra-n-butylammonium hydroxide (TBAH); tetra-n-butylammonium iodide (TBAI); and tetra-ethylammonium chloride hydrate.
It will be appreciated that, notwithstanding the above-stated preferences as to the particular phase transfer catalysts which are selected for use in the preparation processes of the present invention, that there are a significant number of phase transfer catalysts which are known in the art and which are suitable for use in the present invention. The artisan will be well aware of the identity of such phase transfer catalysts as well as the appropriate steps by which their effectiveness in the preparation processes of the present invention may be demonstrated. For example, among phase transfer catalysts known in the art, the following are suitable for use in the preparation processes of the present invention: cetyltrimethylammonium bromide (CTMAB); dibenzo-18-crown-6 (DB-18-c-6); dicydohexano-18-crown-6 (DC-18-c-6); 18-crown-6 (18-c-6); (xe2x88x92)-N-dodecyl-Nmethylephedrinium bromide (DMCOH); hexamethyl phosphoric triamide (HMPT); cetylpyridinium bromide (NCPB); Nbenzylquininium chloride (QUIBEC);
tetra-n-butylammonium bromide (TBAB); tetra-n-butylammonium chloride (TBAC); tetra-n-butylammonium hydroxide (TBAH); tetra-n-butylammonium hydrogen sulfate (TBAHS); tetra-n-butylammonium iodide (TBAI); tetra-ethylammonium chloride hydrate (TEAC); tri-n-butylamine (TBA); benzyltributylammonium bromide (TBBAB); hexadecyltributylphosphonium bromide (TBHDPB); benzyltriethylammonium bromide (TEBAB); benzyltriethylammonium chloride (TEBA); hexadecyltriethylammonium chloride (TEHDAC); tetramethylammonium chloride (TMAC); hexadecyltrimethylammonium chloride (TMHDAC); and octyltrimethylammonium chloride (TMOAC).
The main mechanistic principle of phase transfer catalysis systems is continuous formation of lipophilic ion pairs of desired anions, with lipophilic cations supplied by the catalysts. The anions are thereby able to enter nonpolar organic media, in which the desired reaction takes place. Typical sources of lipophilic cations, which can act as catalysts in such systems, are tetraalkylammonium and other onium salts, crown ethers, cryptands, poly(ethylene glycol) ethers, and so forth. The fundamental nature of phase transfer catalysis is formation of lipophilic ion pairs, which can be found in nonpolar media. With highly lipophilic cations even small inorganic anions form such ion pairs. Phase transfer catalysis can function only in heterogeneous, mostly two-phase systems. In such systems an organic phase contains organic reactants and the catalyst, e.g., a lipophilic tetraalkylammonium chloride, whereas an aqueous, or in general inorganic, phase contains salts of desired anions or a base which can generate organic anions from corresponding precursors located in the organic phase.
In these systems catalysis consists of the transfer of the anions from the inorganic phase, or alternatively organic anions generated at the interface, to the organic phase, where they enter into the desired reaction, whereas the liberated catalyst can bring another anion into the organic phase. By continuous repetition of this action, 1 mol of the catalyst can promote conversion of  greater than 100 mols or reactants. Depending upon the state of aggregation, kinds of anions, and some other factors, it is possible to differentiate a few variants of the above-described phase transfer catalytic process. Notwithstanding this, the skilled artisan will be able to readily adapt the basic requirements for carrying out phase transfer catalysis to the preparation processes of the present invention
Returning now to the description of the preparation processes of the present invention, after the above-described reaction mixture is formed, it is heated to reflux under a nitrogen atmosphere. Under most ambient conditions, the reflux temperature of the reaction mixture will be from 120xc2x0 to 140xc2x0 C., usually from 125xc2x0 to 135xc2x0 C., and most usually 130xc2x0 C.
It is necessary to heat the reaction mixture at the lower above-recited temperatures for a considerable period of time, from 12 to 30 hours, preferably from 16 to 24 hours, most preferably 18 to 20 hours. However, at the higher above-recited temperatures, the reaction proceeds more rapidly, and it is necessary to heat the reaction mixture for much shorter periods of time, from xc2xd to 4 hours, usually xc2xe to 3 hours, and most typically from 1 to 2 hours.
The selection of a suitable temperature and time for carrying the reaction to completion are within the skill of the artisan knowledgeable in methods of organic synthesis. Isolation of the product of the above-described process, e.g., by vacuum filtration, washing with water, and drying in a vacuum oven, is accomplished using convention procedures which are likewise a matter of ordinary skill in the art. As further guidance for the artisan, there is provided herein the following table of values demonstrating different process yield results which have been obtained with solid sodium hydroxide mediated aryl fluoride displacements by 2-methylimidazole:
It will be noted that in the above-recited process of the present invention, that one of the key reactants is the compound of Formula (2.0.0): 
This compound is also a novel intermediate of the present invention, tetrahydro-4-[3-(4-fluorophenyl) thio]phenyl-2H-pyran-4-carboxamide. In order to carry out the above-recited process of the present invention, it is thus necessary to provide a process by which this novel a reactant intermediate itself may be prepared. Accordingly, there follows a description of another process of the present invention by means of which the compound of Formula (2.0.0) is produced.
The present invention is further concerned with a process for preparing a compound of Formula (2.0.0): 
One of the preferred processes of the present invention for preparing the novel intermediate of Formula (2.0.0) may be illustrated by the following Synthesis Scheme (10.0.1): 
where X, M, and R5 all have the same meaning as defined elsewhere herein.
Accordingly, the above-mentioned process of the present invention illustrated in Synthesis Scheme (10.0.1) may be carried out by:
(a) establishing a reaction mixture consisting of
(1) tetrahydro-4-(3-bromo- or iodo-phenyl)-2H-pyran-4-nitrile of Formula (3.0.0): 
where X is bromo or iodo;
and
(2) 4-fluorothiophenol of Formula (4.0.0): 
(3) in a solvent consisting of a straight or branched chain aliphatic alcohol having a total of from 2 to 7 carbon atoms, optionally as an aqueous mixture thereof; and more preferably where said alcohol is a secondary alcohol selected from the group consisting of iso-propyl alcohol, sec-butyl alcohol, iso-pentyl alcohol, and 2-heptanol, optionally as an aqueous mixture of said secondary alcohol;
(4) in the presence of strong base of Formula (5.0.0):
Mxe2x80x94Oxe2x80x94R5xe2x80x83xe2x80x83(5.0.0)
where
M is an alkali metal, Group 1/la element, selected from the group consisting of lithium, Li; sodium,Na; potassium, K; rubidium, Rb; and cesium, Cs; and
R5 is hydrogen, H; or straight or branched chain (C1-C4) alkyl; preferably a member selected from the group consisting of lithium hydroxide, LiOH; sodium hydroxide, NaOH; potassium hydroxide, KOH; rubidium hydroxide, RbOH; cesium hydroxide, CsOH; lithium methoxide, LiOCH3; sodium methoxide, NaOCH3; potassium methoxide, KOCH3; rubidium methoxide, RbOCH3; cesium methoxide, CsOCH3; lithium ethoxide, LiOCH2CH3; sodium ethoxide, NaOCH2CH3; potassium ethoxide, KOCH2CH3; rubidium ethoxide, RbOCH2CH3; cesium ethoxide, CsOCH2CH3; lithium tert-butoxide, LiOC(CH3)3; sodium tert-butoxide, NaOC(CH3)3; potassium teit-butoxide, KOC(CH3)3; rubidium tert-butoxide, RbOC(CH3)3; and cesium tert-butoxide, CsOC(CH3)3; including mixtures of the above;
and further
(5) in the presence of a transition metal catalyst comprising a palladium metal complex, preferably one which is a member selected from the group consisting of
tetrakis(triphenylphosphine)palladium(0), [(C6H5)3P]4Pd(0);
tetrakis(methyldiphenylphosphine)palladium(0), [(C6H5)2PCH3]4Pd(0);
trans-dichlorobis(methyldiphenylphosphine)palladium(II), [(C6H5)2PCH3]2PdCl2;
dichlorobis[methylenebis(diphenylphosphine)]dipalladiumdichloromethane adduct;
dichlorobis(triphenylphosphine)palladium(II), [(C6H5)3P]2PdCl2;
tris(dibenzylideneacetone)dipalladium(0)-chloroform adduct, (C6H5CHxe2x95x90CHCOCHxe2x95x90CHC6H5)3Pd2.CHCl3;
bis(dibenzylideneacetone)palladium(0), (C6H5CH=CHCOCH=CHC6H5)2Pd;
[1,1xe2x80x2-bis(diphenylphosphino)ferrocene]dichloropalladium(II), complex with dichloromethane
bis[1,2-bis(diphenylphosphino)ethane]palladium(II); and
(xcfx80-allyl)palladium(II) chloride dimer;
followed by
(b) heating said reaction mixture, preferably at reflux, preferably for a period of from 12 to 36 hours, more preferably from 18 to 24 hours; whereby there is produced said compound of Formula (2.0.0) which is optionally isolated using conventional separation techniques.
The above-described process is one which prepares an asymmetrically substituted diarylether. At the same time, the reaction which takes place also results in the hydrolysis of the nitrile substituent to the corresponding carboxamide substituent. It has been found that several factors are important in securing completion of the above-described process with acceptable yields of the novel intermediate of Formula (2.0.0).
One such factor is the solvent in which the reaction involved is carried out. The solvent consists of a straight or branched chain aliphatic alcohol having a total of from 2 to 7 carbon atoms. The alcohol solvent may also be used in admixture with water, i.e., as an aqueous mixture of the alcohol in suitable proportions. While the alcohol solvent and water are miscible in almost all proportions, it has been found desirable to maintain the volume to volume ratio of alcohol to water, respectively, in the range of from 25 to 1, to 3 to 1, preferably in the range of from 10 to 1; to 5 to 1.
It has also been found that the most suitable straight or branched chain aliphatic alcohol having a total of from 2 to 7 carbon atoms, for use as the solvent in the process of the present invention is a secondary alcohol selected from the group consisting of isopropyl alcohol, sec-butyl alcohol, isopentyl alcohol, and 2-heptanol. Of these preferred secondary alcohols, the isopropyl alcohol is the most preferred. The above-mentioned secondary alcohols are also optionally utilized as an aqueous mixture, as described in detail above.
It will be appreciated that the reaction temperature employed in the above-described process of the present invention can be regulated by choosing the alcoholic solvent, depending in turn on the degree of reactivity of the substrate. For example, for the reactant of Formula (3.0.0), where X has the meaning iodo, it has been found that the reaction can be carried out smoothly in refluxing isopropyl alcohol. For the reactant of Formula (3.0.0), where X has the meaning bromo, it has been found that the reaction can be carried out smoothly in refluxing sec-butyl alcohol. It will also be appreciated that the reaction involving aryl iodide in the above-described process of the present invention, i.e., where X has the meaning iodo in the reactant of Formula (3.0.0), proceeds rapidly and can be completed in a period of a few hours"" time. The reaction involving aryl bromide, on the other hand, i.e., where X has the meaning bromo in the reactant of Formula (3.0.0), proceeds more slowly than the reaction involving aryl iodide, and heating of the reaction mixture for a significantly longer period of time, more than 10 hours, is required to complete the reaction. However, prolonged heating of the reaction mixture in the case of either reaction, does not adversely affect the yield of the resulting diaryl thioether, ie., diaryl sulfide.
Another such factor is the use of a strong base of Formula (5.0.0):
Mxe2x80x94Oxe2x80x94R5xe2x80x83xe2x80x83(5.0.0)
where M is an alkali metal, Group 111a element, selected from the group consisting of lithium, Li; sodium,Na; potassium, K; rubidium, Rb; and cesium, Cs; and R5 is hydrogen, H; or straight or branched chain (C1-C4) alkyl. Preferred strong bases comprise a member selected from the group consisting of lithium hydroxide, LiOH; sodium hydroxide, NaOH; potassium hydroxide, KOH; rubidium hydroxide, RbOH; cesium hydroxide, CsOH; lithium methoxide, LiOCH3; sodium methoxide, NaOCH3; potassium methoxide, KOCH3; rubidium methoxide, RbOCH3; cesium methoxide, CsOCH3; lithium ethoxide, LiOCH2CH3; sodium ethoxide, NaOCH2CH3; potassium ethoxide, KOCH2CH3; rubidium ethoxide, RbOCH2CH3; cesium ethoxide, CsOCH2CH3; lithium tert-butoxide, LiOC(CH3)3; sodium tert-butoxide, NaOC(CH3)3; potassium tert-butoxide, KOC(CH3)3; rubidium tert-butoxide, RbOC(CH3)3; and cesium tert-butoxide, CsOC(CH3)3.
The above-mentioned strong bases may be used in the form of mixtures thereof, but it is preferred to employ only a single strong base. More preferred among the above-recited strong bases are sodium hydroxide, NaOH; potassium hydroxide, KOH; sodium ethoxide, NaOCH2CH3; and potassium tert-butoxide, KOC(CH3)3.
A still further factor in achieving satisfactory completion of the above-described process of the present invention is the use of a transition metal catalyst comprising palladium metal complexes. Included among the palladium metal complexes which are preferred for use in the process of the present invention, are more preferred species of such catalysts which are used in the above-described process. Said more preferred species is a member selected from the group consisting of:
tetrakis(triphenylphosphine)palladium(0): [(C6H5)3P]4Pd(0);
tetrakis(methyldiphenylphosphine)palladium(0): [(C6H5)2PCH3]4Pd(0);
trans-dichlorobis(methyldiphenylphosphine)palladium(II): [(C6H5)2PCH3]2PdCl2;
dichlorobis[methylenebis(diphenylphosphine)]dipalladium-dichloromethane adduct of Formula (6.0.0): 
dichlorobis(triphenylphosphine)palladium(II): [(C6H5)3P]2PdCl2;
tris(dibenzylideneacetone)dipalladium(0)-chloroform adduct: (C6H5CHxe2x95x90CHCOCHxe2x95x90CHC6H5)3Pd2.CHCl3;
bis(dibenzylideneacetone)palladium(0): (C6H5CHxe2x95x90CHCOCHxe2x95x90CHC6H5)2Pd;
[1,1xe2x80x2-bis(diphenylphosphino)ferrocene]dichloropalladium(II), complex with dichloromethane, of Formula (6.1.0): 
bis[1,2-bis(diphenylphosphino)ethane]palladium(II) of Formula (6.2.0): 
and
(xcfx80-allyl)palladium(II) chloride dimer of Formula (6.3.0): 
Of the palladium metal complexes described above, the most preferred is tetrakis(triphenylphosphine)palladium(0), [(C6H5)3P]4Pd(0). This preferred catalyst may be used with or without a ligand. When a ligand is used with [(C6H5)3P]4Pd(0), preferred ligands are triphenylphosphine (TPP), ethylenebis(diphenylphosphine), and tri-(2-tolyl)phosphine, The preferred ratio of catalyst to ligand is approximately 1:2 molar equivalents, but the artisan will be aware that the use of excessive amounts of ligand can lead to a reduction in the overall yield of the reaction in which such a ligand is being used. In the same manner, the other palladium metal complexes used as catalysts in the processes of the present invention are used both with and without a ligand. The use of a ligand can affect the yield of final product, ie., the compound of Formula (2.0.0), as is illustrated by the table of values immediately following showing yields from the above-described process of the present invention where different palladium metal complexes are used without a ligand or with one of a variety of ligands.
The above-described ligands as well as others well known in the art may be employed with the palladium metal complexes used as catalysts in the process of the present invention.
As pointed out further above, a particular advantage of the above-described process is that in the course of carrying out the reaction under the prescribed conditions, whether these are suitable or preferred, the nitrile moiety on the compound of Formula (3.0.0) is hydrolyzed to the corresponding carboxamide group which appears on the final product, a compound of Formula (1.0.0). Nevertheless, the present invention also affords an alternative process of preparing the novel intermediate, a compound of Formula (2.0.0), in which said nitrile moiety is first hydrolyzed to the corresponding carboxamide, thereby producing a compound of Formula (3.1.0). After this synthesis step has been carried out, the carboxamide compound of Formula (3.1.0) is reacted with the fluorothiophenol compound of Formula (4.0.0) to produce said novel intermediate of Formula (2.0.0).
It will be further noted that the second step of the above-mentioned alternative process is carried out in a fashion which is essentially the same as that illustrated in Scheme 2 above.
Consequently, the present invention is also concerned with an alternative process for preparing a compound of Formula (2.0.0): 
which may be illustrated by Synthesis Scheme (10.1.0) as follows: 
where X, M, and R5 all have the same meaning as defined elsewhere herein.
The alternative process of the present invention illustrated in Synthesis Scheme (10.1.0) may be carried out by:
(a) establishing a reaction mixture consisting of
(1) tetrahydro-4-(3-bromo- or iodo-phenyl)2H-pyran-4-nitrile of Formula (3.0.0): 
where X is bromo or iodo;
(2) in a solvent consisting of a straight or branched chain aliphatic alcohol having a total of from 2 to 7 carbon atoms, optionally as an aqueous mixture thereof; and more preferably where said alcohol is a secondary alcohol selected from the group consisting of iso-propyl alcohol, sec-butyl alcohol, isopentyl alcohol, and 2-heptanol, optionally as an aqueous mixture of said secondary alcohol;
(3) in the presence of strong base of Formula (5.0.0):
Mxe2x80x94Oxe2x80x94R5xe2x80x83xe2x80x83(5.0.0)
where
M is an alkali metal, Group 1/la element, selected from the group consisting of lithium, Li; sodium,Na; potassium, K; rubidium, Rb; and cesium, Cs; and
R5 is hydrogen, H; or straight or branched chain (C1-C4) alkyl; preferably a member selected from the group consisting of lithium hydroxide, LIOH; sodium hydroxide, NaOH; potassium hydroxide, KOH; rubidium hydroxide, RbOH; cesium hydroxide, CSOH; lithium methoxide, LiOCH3; sodium methoxide, NaOCH3; potassium methoxide, KOCH3; rubidium methoxide, RbOCH3; cesium methoxide, CsOCH3; lithium ethoxide, LiOCH2CH3; sodium ethoxide, NaOCH2CH3; potassium ethoxide, KOCH2CH3; rubidium ethoxide, RbOCH2CH3; cesium ethoxide, CsOCH2CH3; lithium tert-butoxide, LiOC(CH3)3; sodium tert-butoxide, NaOC(CH3)3; potassium tert-butoxide, KOC(CH3)3; rubidium tert-butoxide, RbOC(CH3)3; and cesium tert-butoxide, CsOC(CH3)3; including mixtures of the above;
followed by
(b) heating said reaction mixture, preferably at reflux, preferably for a period of from 3 to 8 hours, more preferably from 5 to 6 hours; whereby there is produced a compound of Formula (3.1.0): 
where X is bromo or iodo;
followed by
(c) forming a reaction mixture consisting of said compound of Formula (4.0.0) and 4-fluorothiophenol of Formula (4.0.0): 
(1) in a solvent consisting of a straight or branched chain aliphatic alcohol having a total of from 2 to 7 carbon atoms, optionally as an aqueous mixture thereof; and more preferably where said alcohol is a secondary alcohol selected from the group consisting of iso-propyl alcohol, sec-butyl alcohol, iso-pentyl alcohol, and 2-heptanol, optionally as an aqueous mixture of said secondary alcohol;
(2) in the presence of strong base of Formula (5.0.0):
Mxe2x80x94Oxe2x80x94R5xe2x80x83xe2x80x83(5.0.0)
where
M is an alkali metal, Group lila element, selected from the group consisting of lithium, Li; sodium, Na; potassium, K; rubidium, Rb; and cesium, Cs; and
R5 is hydrogen, H; or straight or branched chain (C1-C4) alkyl; preferably a member selected from the group consisting of lithium hydroxide, LIOH; sodium hydroxide, NaOH; potassium hydroxide, KOH; rubidium hydroxide, RbOH; cesium hydroxide, CsOH; lithium methoxide, LiOCH3; sodium methoxide, NaOCH3; potassium methoxide, KOCH3; rubidium methoxide, RbOCH3; cesium methoxide, CsOCH3; lithium ethoxide, UiOCH2CH3; sodium ethoxide, NaOCH2CH3; potassium ethoxide, KOCH2CH3; rubidium ethoxide, RbOCH2CH3; cesium ethoxide, CsOCH2CH3; lithium tert-butoxide, LiOC(CH3)3; sodium tert-butoxide, NaOC(CH3)3, potassium teft-butoxide, KOC(CH3)3; rubidium tert-butoxide, RbOC(CH3)3; and cesium tert-butoxide, CsOC(CH3)3; including mixtures of the above;
and further
(3) in the presence of a transition metal catalyst comprising a member independently selected from the group consisting of palladium metal complexes; preferably wherein said palladium metal complex is a member selected from the group consisting of
tetrakis(triphenylphosphine)palladium(0), [(C6H5)3P]4Pd(0);
tetrakis(methyldiphenylphosphine)palladium(0), [(C6H5)2PCH3]4Pd(0);
trans-dichlorobis(methyldiphenylphosphine)palladium(II), [(C6H5)2PCH3]2PdCl2;
dichlorobis[methylenebis(diphenylphosphine)]dipalladium-dichloromethane adduct;
dichlorobis(triphenylphosphine)palladium(II), [(C6H5)3P]2PdCl2;
tris(dibenzylideneacetone)dipalladium(0)-chloroform adduct, (C6H5CHxe2x95x90CHCOCHxe2x95x90CHC6H5)3Pd2.CHCl3;
bis(dibenzylideneacetone)palladium(0), (C6H5CHxe2x95x90CHCOCHxe2x95x90CHC6H5)2Pd;
[1,1xe2x80x2-bis(diphenylphosphino)ferrocene]dichloropalladium(II), complex with dichloromethane
bis[1,2-bis(diphenylphosphino)ethane]palladium(II); and
(xcfx80-allyl)palladium(II) chloride dimer;
followed by
(d) heating said reaction mixture, preferably at reflux, preferably for a period of from 5 to 15 hours, more preferably from 8 to 10 hours; whereby there is produced said compound of Formula (2.0.0).
One of the key aspects of the preparation processes of the present invention is an improved means of producing the known 5-lipoxygenase inhibitory compound of Formula (1.0.0): 
This improved process involves most of the above-described preferred embodiments of the present invention, and may be illustrated by Synthesis Scheme (10.3.1) as follows 
The improved process of the present invention illustrated in Synthesis Scheme (10.3.0) is deemed to comprise a total of six embodiments of the present invention. The first embodiment is Step a, which is the first step illustrated in Synthesis Scheme (10.3.0), and is a process for preparing the novel intermediate of the present invention of Formula (2.0.0). The second embodiment is Step b, which is the second or middle step illustrated in Synthesis Scheme (10.3.0), and is a process for preparing the known 5-lipoxygenase inhibitory compound of Formula (1.0.0), as the compound per se. The third embodiment is Step c or Step d, which is the last step in Synthesis Scheme (10.3.0), and is a process for preparing the mesylate salt of said known compound of Formula (1.0.0). The fourth embodiment is Step b+Step c or d. The fifth embodiment is Step a+Step b. The sixth embodiment is Step a+Step b+Step c or d.
For the sake of brevity, only the second and sixth embodiments are described in detail below. Accordingly, the second above-mentioned embodiment, Step b in Synthesis Scheme (10.3.1), is carried out as follows:
(a) establishing a reaction mixture consisting of
(1) tetrahydro-4-[3-(4-fluorophenyl)-thio]phenyl-2H-pyran-4-carboxamide of Formula (2.0.0): 
and
(2) 2-methylimidazole;
(3) in an aprotic solvent, preferably a member selected from the group consisting essentially of hexane; 1,4-dioxane; carbon tetrachloride; benzene; toluene; xylenes; diethyl ether; chloroform; ethyl acetate; tetrahydrofuran (THF); methylene chloride; hexamethylphosphoric triamide (HMPT); nitromethane; N,N-dimethylformamide (DMF); acetonitrile; sulfolane; and dimethylsulfoxide (DMSO); more preferably dimethylsulfoxide (DMSO);
(4) in the presence of a strong base in solid form selected from the group consisting of sodium hydroxide, NaOH; and potassium hydroxide, KOH;
and optionally
(5) in the presence of a catalytic amount of cesium carbonate, Cs2CO3, or of a phase transfer catalyst, preferably a member selected from the group consisting of cetyltrimethylammonium bromide (CTMAB); dibenzo-18-crown-6 (DB-18-c-6); dicyclohexano-18-crown-6 (DC-18-c-6); 18-crown-6 (18-c-6); (xe2x88x92)-N-dodecyl-N-methylpyridinium bromide (DMCOH); hexamethyl phosphoric triamide (HMPT); cetylpyridinium bromide (NCPB); N-benzylquininium chloride (QUIBEC); tetra-n-butylammonium bromide (TBAB); tetra-n-butylammonium chloride (TBAC); tetra-n-butylammonium hydroxide (TBAH); tetra-n-butylammonium hydrogen sulfate (TBAHS); tetra-n-butylammonium iodide (TBAI); tetra-ethylammonium chloride hydrate (TEAC); tri-n-butylamine (TBA); benzyitributylammonium bromide (TBBAB); hexadecyltributylphosphonium bromide (TBHDPB); benzyltriethylammonium bromide (TEBAB); benzyitriethylammonium chloride (TEBA); hexadecyltriethylammonium chloride (TEHDAC); tetramethylammonium chloride (TMAC); hexadecyltrimethylammonium chloride (TMHDAC); and octyltrimethylammonium chloride (TMOAC); and more preferably a quatemary ammonium salt or a phosphonium salt comprising a member of the above-recited group;
followed by
(b) heating said reaction mixture, preferably at reflux, preferably from 115xc2x0 to 145xc2x0 C., more preferably from 125xc2x0 to 130xc2x0 C., under a nitrogen atmosphere, preferably for from 12 to 30 hours, more preferably for from 17 to 24 hours; whereby there is produced said compound of Formula (1.3.0).
The above-mentioned sixth embodiment, Step a+Step b+Step c of Synthesis Scheme (10.3.0), of the present invention is a process for preparing a substantially pure mesylate salt of Formula (1.0.1): 
comprising:
(a) preparing a compound of Formula (2.0.0): 
comprising:
(1) establishing a reaction mixture consisting of
(i) tetrahydro-4-(3-bromo-phenyl)-2H-pyran-4-nitrile of Formula (3.2.0): 
and
(ii) 4-fluorothiophenol of Formula (4.0.0): 
(iii) in a solvent selected from the group consisting of isopropyl alcohol, sec-butyl alcohol, isopentyl alcohol, and 2-heptanol, optionally as an aqueous mixture thereof;
(iv) in the presence of a strong base selected from the group consisting of sodium hydroxide, NaOH; and potassium hydroxide, KOH;
and further
(v) in the presence of a catalyst comprising a member independently selected from the group consisting of the following palladium metal complexes:
tetrakis(triphenylphosphine)palladium(0), [(C6H5)3P]4Pd(0);
tetrakis(methyldiphenylphosphine)palladium(0), [(C6H5)2PCH3]4Pd(0);
trans-dichlorobis(methyldiphenylphosphine)palladium(II), [(C6H5)2PCH3]2PdCl2;
dichlorobis[methylenebis(diphenylphosphine)]dipalladium-dichloromethane adduct;
dichlorobis(triphenylphosphine)palladium(II), [(C6H5)3P]2PdCl2;
tris(dibenzylideneacetone)dipalladium(0)-chloroform adduct, (C6H5CHxe2x95x90CHCOCHxe2x95x90CHC6H5)3Pd2.CHCl3;
bis(dibenzylideneacetone)palladium(0), (C6H5CHxe2x95x90CHCOCHxe2x95x90CHC6H5)2Pd;
[1,1xe2x80x2-bis(diphenylphosphino)ferrocene]dichloropalladium(II), complex with dichloromethane
bis[1,2-bis(diphenylphosphino)ethane]palladium(II); and
(xcfx80-allyl)palladium(II) chloride dimer;
followed by
(2) heating said reaction mixture at reflux of from 80xc2x0 to 84xc2x0 C. for a period of from 18 to 30 hours, preferably 24 hours; whereby there is produced said compound of Formula (2.0.0);
(b) establishing a reaction mixture consisting of said compound of Formula (2.0.0) and a compound of Formula (1.3.10): 
(1) in an aprotic solvent selected from the group consisting essentially of tetrahydrofuran (THF); methylene chloride; N,N-dimethylformamide (DMF); and dimethylsulfoxide (DMSO); more preferably dimethylsulfoxide (DMSO);
(2) in the presence of a strong base in solid form selected from the group consisting of sodium hydroxide, NaOH; and potassium hydroxide, KOH;
and optionally
(3) in the presence of a catalytic amount of cesium carbonate, Cs2CO3, or of a phase transfer catalyst, preferably a member selected from the group consisting of cetyltrimethylammonium bromide (CTMAB); dibenzo-18-crown-6 (DB-18-c-6); dicyclohexano-18-crown-6 (DC-18-c-6); 18-crown-6 (18-c-6); (xe2x88x92)-N-dodecyl-N-methylpyridinium bromide (DMCOH); hexamethyl phosphoric triamide (HMPT); cetylpyridinium bromide (NCPB); N-benzylquininium chloride (QUIBEC); tetra-nrbutylammonium bromide (TBAB); tetra-n-butylammonium chloride (TBAC); tetra-n-butylammonium hydroxide (TBAH); tetra-n-butylammonium hydrogen sulfate (TBAHS); tetra-n-butylammonium iodide (TBAI); tetra-ethylammonium chloride hydrate (TEAC); tri-n-butylamine (TBA); benzyltributylammonium bromide (TBBAB); hexadecyltributylphosphonium bromide (TBHDPB); benzyltriethylammonium bromide (TEBAB); benzyftriethylammonium chloride (TEBA); hexadecyltriethylammonium chloride (TEHDAC); tetramethylammonium chloride (TMAC); hexadecyltrimethylammonium chloride (TMHDAC); and octyltrimethylammonium chloride (TMOAC); and more preferably a quatemary ammonium salt or a phosphonium salt comprising a member of the above-recited group;
followed by
(c) heating said reaction mixture at reflux, under a nitrogen atmosphere; whereby there is produced a compound of Formula (1.0.0): 
followed by
(d) forming a concentrated methanol solution of said compound of Formula (1.0.0) followed by filtering of the solution, preferably through activated carbon, to the filtrate of which there is then added methanesulfonic acid, MeSO3H; followed by further concentration and the addition of ethyl acetate ad seriatim until a crystalline product is isolated comprising substantially pure mesylate salt of Formula (1.0.1) 
or, alternatively, followed by
(e) forming a concentrated methanol solution of said compound of Formula (1.0.0) to which there is then added methanesulfonic acid, MeSO3H; followed by filtering of the mixture, preferably through activated carbon, after which there follows further concentration and the addition of ethyl acetate ad seratim until a crystalline product is isolated comprising substantially pure mesylate salt of Formula (1.0.1).
The preferred method of mesylate salt formation is that of forming a concentrated methanol solution of said compound of Formula (1.0.0) which also contains methanesulfonic acid, MeSO3H; followed by filtration. It has been found that this method results in a significant reduction in process volumes and a reduction in the amount of residual palladium in the final product. The primary purpose of the above-described methanol recrystallization during formation of the mesylate salt of Formula (1.0.1) is to remove any residual palladium from the final product that may not have been removed during the filtration step, which is preferably carried out using activated carbon.
It will be appreciated that the above-described process for preparing the mesylate salt of the compound of Formula (1.0.0) may be readily adapted using the skills and knowledge available in the art, to prepare other, analogous sulfonate salts of the compound of Formula (1.0.0), especially the tosylate salt.